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Objective: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited treatment options. This study aimed to investigate the effects of Lycium barbarum extract (LBE), a Chinese herb, on the central nervous system (CNS)—including the retina, brain, and spinal cord—in 5xFAD transgenic mice after the onset of AD. Methods: Starting at 6 months of age, 5xFAD mice received daily intragastric gavage of LBE (2 g/kg) for 2 months. At 8 months, behavioral tests were conducted to assess cognition, motor function, and visual function. These included the Morris water maze, novel object recognition, and Y‐maze tests for cognition; the beam walking balance and clasping tests for motor function; and electroretinogram (ERG) for visual function. Immunohistochemistry, western blotting, and ELISA were used to evaluate Aβ deposition, microglial morphology, neuroinflammation, and neuroprotective signaling pathways. Primary microglia and the IMG cell line were used to study LBE's effects on Aβ uptake and degradation in vitro. Results: After 2 months of LBE treatment, the decline in cognition, motor, and visual functions in 5xFAD mice was significantly slowed. Microglia in the brain, spinal cord, and retina exhibited a neuroprotective state, with reduced Aβ deposition, decreased inflammatory cytokine levels (e.g., TNF‐α, IL‐1β, IL‐6), increased Arg‐1/iNOS ratio, and enhanced phagocytic capacity. LBE also promoted Aβ uptake and degradation in primary microglia and the IMG cell line. Neuroprotective signals such as p‐Akt, p‐Erk1/2, and p‐CREB were elevated. Additionally, LBE treatment restored synaptic protein expression and enhanced neuroplasticity. Conclusion: The findings suggest that LBE treatment can enhance neuroplasticity, reduce systemic inflammation, and improve phagocyte clearance of Aβ deposition via inducing a neuroprotective microglial phenotype throughout CNS. As an upper‐class Chinese medicine, appropriate intake of LBE may serve as a beneficial antiaging strategy for AD. [ABSTRACT FROM AUTHOR]